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Dong H, Li S, Peng Y, Zhang X, Zheng J, Xue C, Zheng Y, Yu Y, Lu X, Hu Z, Cui H. Durvalumab‑induced type 1 diabetes mellitus in lung adenocarcinoma: A case report and literature review. Oncol Lett 2025; 29:277. [PMID: 40247987 PMCID: PMC12005073 DOI: 10.3892/ol.2025.15023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 03/19/2025] [Indexed: 04/19/2025] Open
Abstract
Immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM) is a rare adverse reaction associated with durvalumab. Among the adverse reactions to durvalumab, the incidence of new-onset diabetes is relatively rare, occurring in ~0.2% of cases. The present study reports the case of a 62-year-old woman who developed ICI-T1DM following two cycles of durvalumab, presenting with thirst, polydipsia and polyuria. Laboratory examinations (glycated hemoglobin and glutamic acid decarboxylase antibody), along with consultations from an endocrinologist, led to the patient being diagnosed with ICI-T1DM. Immunotherapy was discontinued, and insulin replacement therapy was initiated. Blood glucose levels were closely monitored using a subcutaneous meter. The onset of diabetic ketoacidosis (DKA) was prevented due to timely treatment. In conclusion, medical oncologists need to be aware that durvalumab, an immunotherapy agent, can induce ICI-T1DM. Therefore, regular monitoring of blood glucose levels and collaborative consultations with endocrinologists are essential for an accurate diagnosis when elevated blood sugar levels are detected. The prompt diagnosis of ICI-T1DM is crucial to prevent the occurrence of DKA.
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Affiliation(s)
- Huijing Dong
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Shengfu Li
- Department of Tuberculosis, Tai Yuan Fourth Peoples (Tuberculosis) Hospital, Taiyuan, Shanxi 030053, P.R. China
| | - Yanmei Peng
- Department of Oncology, Fangshan Hospital Beijing University of Chinese Medicine, Beijing 102400, P.R. China
| | - Xu Zhang
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Jiabin Zheng
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Chongxiang Xue
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Yumin Zheng
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Yixuan Yu
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Xingyu Lu
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Zixin Hu
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Huijuan Cui
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, P.R. China
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2
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Almawash S. Revolutionary Cancer Therapy for Personalization and Improved Efficacy: Strategies to Overcome Resistance to Immune Checkpoint Inhibitor Therapy. Cancers (Basel) 2025; 17:880. [PMID: 40075727 PMCID: PMC11899125 DOI: 10.3390/cancers17050880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 02/09/2025] [Accepted: 02/12/2025] [Indexed: 03/14/2025] Open
Abstract
Cancer remains a significant public health issue worldwide, standing as a primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...].
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Affiliation(s)
- Saud Almawash
- Department of Pharmaceutics, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia
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3
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Dugbartey GJ, Alornyo KK, Dapaa-Addo CO, Botchway E, Kwashie EK, Harley Y. Alpha-lipoic acid: A promising pharmacotherapy seen through the lens of kidney diseases. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2024; 7:100206. [PMID: 39524210 PMCID: PMC11550178 DOI: 10.1016/j.crphar.2024.100206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 10/09/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Kidney diseases have rapidly increased in prevalence over the past few decades, and have now become a major global public health concern. This has put economic burden on the public healthcare system and causing significant morbidity and mortality worldwide. Unfortunately, drugs currently in use for the management of kidney diseases have long-term major adverse effects that negatively impact the quality of life of these patients, hence making these drugs a "necessary evil". In recent times, antioxidant therapy has been explored as a potential pharmacological avenue for treatment of kidney diseases, and could offer a better therapeutic option with less adverse effect profile. One of such antioxidants is alpha-lipoic acid (ALA), a sulphur-containing multifunctional antioxidant that is endogenously produced by lipoic acid synthase in the mitochondria of many tissues, including the kidney. Burgeoning evidence indicates that ALA is showing clinical promise in the treatment and pharmacological management of many kidney diseases through its antioxidant and other therapeutic properties by activating several protective mechanisms while inhibiting deleterious signaling pathways. In this review, we present ALA as a potent naturally occurring antioxidant, its mitochondrial biosynthesis and pharmacological properties. In addition, we also discuss within the limit of present literature, ALA and its underlying molecular mechanisms implicated in experimental and clinical treatment of various kidney conditions, and thus, may offer nephrologists an additional and/or alternative avenue in the pharmacological management and treatment of kidney diseases while giving hope to these patients.
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Affiliation(s)
- George J. Dugbartey
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
- Department of Physiology and Pharmacology, Accra College of Medicine, East Legon, Accra, Ghana
- Department of Surgery, Division of Urology, London Health Sciences Centre, Western University, N6A 5C1, London, ON, Canada
- Matthew Mailing Centre for Translational Transplant Studies, London Health Sciences Centre, Western University, N6A 5C1, London, ON, Canada
| | - Karl K. Alornyo
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana
| | | | - Emmanuel Botchway
- Department of Physiology and Pharmacology, Accra College of Medicine, East Legon, Accra, Ghana
| | - Emmanuel K. Kwashie
- Department of Physiology and Pharmacology, Accra College of Medicine, East Legon, Accra, Ghana
| | - Yvonne Harley
- Department of Physiology and Pharmacology, Accra College of Medicine, East Legon, Accra, Ghana
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4
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Ni R, Hu Z, Tao R. Advances of immune-checkpoint inhibition of CTLA-4 in pancreatic cancer. Biomed Pharmacother 2024; 179:117430. [PMID: 39260322 DOI: 10.1016/j.biopha.2024.117430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 09/05/2024] [Accepted: 09/05/2024] [Indexed: 09/13/2024] Open
Abstract
Targeting checkpoints for immune cell activation has been acknowledged known as one of the most effective way to activate anti-tumor immune responses. Among them, drugs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are approved for clinical treatment though several more are in advanced stages of development, which demonstrated durable response rates and manageable safety profile. However, its therapy efficacy is unsatisfactory in pancreatic cancer (PC), which can be limited by the overall condition of patients, the pathological type of PC, the expression level of tumor related genes, etc. To improve clinical efficiency, various researches have been conducted, and the efficacy of combination therapy showed significantly improvement compared to monotherapy. This review analyzed current strategies based on anti-CTLA-4 combination immunotherapy, providing totally new idea for future research.
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Affiliation(s)
- Ran Ni
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China; General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zhiming Hu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China; Department of Hepatobiliary & Pancreatic Surgery, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China.
| | - Ran Tao
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
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5
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Greene A, Penner S, Kunesh J, Altaf A, McGrade W, Niu J. Pembrolizumab induced type 1 diabetes mellitus in a patient with metastatic melanoma and literature review on steroids as a treatment option. J Oncol Pharm Pract 2024; 30:1084-1088. [PMID: 38544442 DOI: 10.1177/10781552241241493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
OBJECTIVE We report a case of a 77-year-old male with metastatic melanoma who developed immune-checkpoint-inhibitor (ICI) induced type 1 diabetes mellitus (T1DM) after seven months of pembrolizumab treatment and required life-long insulin use. This prompted a literature review of best practice guidelines for long-term management of checkpoint-inhibitor induced T1DM including oral steroids as a treatment option similar to other ICI adverse effects. DATA SOURCES AND SUMMARY A literature search on PubMed was conducted to evaluate the efficacy of steroid treatment ICI-induced T1DM in any cancer type. Search terms consisted of "ipilimumab" OR "nivolumab" OR & "pembrolizumab" OR "immune checkpoint" AND "diabetes" OR "type 1 diabetes" AND "cancer" OR "melanoma" OR "carcinoma OR "sarcoma". Inclusion criteria were case reports published after 2015 in which the patient was diagnosed with ICI-induced T1DM or diabetic ketoacidosis where oral steroids were part of the treatment. Exclusion criteria included oral steroids not used as a treatment modality for T1DM, multiple endocrine comorbidities, no response recorded, and previous history of T1DM. 284 abstracts were found with these search terms of which 33 full-text articles were concluded to be eligible and screened and from which 8 records were included. From these 8 articles, there were 12 cases included. CONCLUSION This literature search suggests that ICI-induced T1DM cannot be reversed by steroids and that insulin must be used permanently for treatment management.
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Affiliation(s)
- Adina Greene
- College of Medicine - Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Scott Penner
- College of Medicine - Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Jacqueline Kunesh
- College of Medicine - Phoenix, University of Arizona, Phoenix, AZ, USA
| | - Amal Altaf
- College of Medicine - Phoenix, University of Arizona, Phoenix, AZ, USA
| | - William McGrade
- Department of Internal Medicine, Banner Health, Sun City, AZ, USA
| | - Jiaxin Niu
- Banner MD Anderson Cancer Center, Gilbert, AZ, USA
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6
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Aldarayseh M, Sodhi SS, Musleh G, Kumar D, Cholankeril M. Unforeseen Complications of Pembrolizumab in Breast Reconstruction Post-Mastectomy. Eur J Case Rep Intern Med 2024; 11:004675. [PMID: 38984194 PMCID: PMC11229478 DOI: 10.12890/2024_004675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 06/10/2024] [Indexed: 07/11/2024] Open
Abstract
A 53-year-old post-menopausal Indian female presented with invasive ductal carcinoma, treated with neoadjuvant chemotherapy and pembrolizumab due to a PD-L1 combined positive score of 5. Following a right mastectomy and axillary dissection, she received a breast expander and AlloDerm™ graft. After resuming pembrolizumab and paclitaxel postoperatively, she developed severe breast redness and high-grade fever, necessitating expander removal due to suspected pembrolizumab-induced complications. This case underscores the unique and severe adverse effects of pembrolizumab on breast reconstruction, highlighting the need for careful monitoring and management in patients undergoing similar treatments. LEARNING POINTS Among patients with early triple-negative breast cancer, the combination of pembrolizumab with neoadjuvant chemotherapy enhances outcomes compared to chemotherapy alone.Early recognition is essential for managing pembrolizumab-induced complications, as demonstrated by the need for expander removal and debridement in this case.The unique adverse effects observed in this case underscore the importance of tailoring cancer treatment plans to individual patients, taking into account the potential risks associated with immunotherapy in the context of reconstructive surgery.
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Affiliation(s)
- Murad Aldarayseh
- Internal Medicine Department, RWJ Barnabas Health/Trinitas Regional Medical Center, Elizabeth, USA
| | - Sohail Singh Sodhi
- Internal Medicine Department, RWJ Barnabas Health/Trinitas Regional Medical Center, Elizabeth, USA
| | - Gamal Musleh
- Internal Medicine Department, RWJ Barnabas Health/Trinitas Regional Medical Center, Elizabeth, USA
| | - Dyuti Kumar
- St George's University School of Medicine, Grenada, West Indies
| | - Michelle Cholankeril
- Internal Medicine Department, RWJ Barnabas Health/Trinitas Regional Medical Center, Elizabeth, USA
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Nagy S, Demory Beckler M, Hussein A, Kesselman MM. The Development of Diabetes and Diabetic Ketoacidosis Following Immunotherapy Treatment: A Systematic Review of Case Reports. Cureus 2024; 16:e57894. [PMID: 38606021 PMCID: PMC11007471 DOI: 10.7759/cureus.57894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 04/09/2024] [Indexed: 04/13/2024] Open
Abstract
As cancer continues to be the leading cause of death worldwide, additional therapeutic options other than traditional platinum-based chemotherapy have become available that target tumor cells in innovative ways. Immunotherapies (e.g., immune checkpoint inhibitors (ICI)) ramp up the immune system to target cancer cells, providing patients with more personalized and tumor cell-specific treatment options. This new age oncological treatment option has been found to provide a more meaningful and stronger alternative to traditional chemotherapy, resulting in longer periods of remission and milder side effects. However, because ICI heightens the immune system, resultant autoimmune conditions can occur. One of the most recently shown adverse effects of ICI are extreme hyperglycemia (i.e., type 1 diabetes) and diabetic ketoacidosis (DKA). To determine the incidence of immunotherapy-induced diabetes, a systematic literature review was performed using CINHAL, EBSCO, MEDLINE, and Web of Science. A total of 403 articles were initially screened, with a final 28 case reports included. The results show that checkpoint inhibitors were found to be most commonly associated with new-onset diabetes as opposed to traditional chemotherapy. Additionally, 41% of patients developed autoimmune diabetes and DKA after being placed on a single therapy of pembrolizumab (targets PD-1: programmed cell death protein 1). However, the pathological process underlying the development of endocrinopathies after treatment with ICI continues to be under investigation.
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Affiliation(s)
- Stephanie Nagy
- Rheumatology, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, USA
| | - Michelle Demory Beckler
- Microbiology and Immunology, Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, USA
| | - Atif Hussein
- Hematology and Oncology, Memorial Cancer Institute, Pembroke Pines, USA
| | - Marc M Kesselman
- Rheumatology, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, USA
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8
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Jo W, Won T, Daoud A, Čiháková D. Immune checkpoint inhibitors associated cardiovascular immune-related adverse events. Front Immunol 2024; 15:1340373. [PMID: 38375475 PMCID: PMC10875074 DOI: 10.3389/fimmu.2024.1340373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 01/19/2024] [Indexed: 02/21/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) are specialized monoclonal antibodies (mAbs) that target immune checkpoints and their ligands, counteracting cancer cell-induced T-cell suppression. Approved ICIs like cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), its ligand PD-L1, and lymphocyte activation gene-3 (LAG-3) have improved cancer patient outcomes by enhancing anti-tumor responses. However, some patients are unresponsive, and others experience immune-related adverse events (irAEs), affecting organs like the lung, liver, intestine, skin and now the cardiovascular system. These cardiac irAEs include conditions like myocarditis, atherosclerosis, pericarditis, arrhythmias, and cardiomyopathy. Ongoing clinical trials investigate promising alternative co-inhibitory receptor targets, including T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT). This review delves into the mechanisms of approved ICIs (CTLA-4, PD-1, PD-L1, and LAG-3) and upcoming options like Tim-3 and TIGIT. It explores the use of ICIs in cancer treatment, supported by both preclinical and clinical data. Additionally, it examines the mechanisms behind cardiac toxic irAEs, focusing on ICI-associated myocarditis and atherosclerosis. These insights are vital as ICIs continue to revolutionize cancer therapy, offering hope to patients, while also necessitating careful monitoring and management of potential side effects, including emerging cardiac complications.
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Affiliation(s)
- Wonyoung Jo
- Department of Biomedical Engineering, Johns Hopkins University, Whiting School of Engineering, Baltimore, MD, United States
| | - Taejoon Won
- Department of Pathobiology, University of Illinois Urbana-Champaign, College of Veterinary Medicine, Urbana, IL, United States
| | - Abdel Daoud
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, United States
| | - Daniela Čiháková
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, United States
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
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Gentzler RD, Mohindra NA, Jalal SI, Reckamp KL, Hall RD, Hanna NH, Chae YK, Koczywas M, Helenowski IB, Patel JD. Phase I/II Trial of Carboplatin, Nab-paclitaxel, and Pembrolizumab for Advanced Non-Small Cell Lung Cancer: Hoosier Cancer Research Network LUN13-175. Oncologist 2024; 29:47-56. [PMID: 37390616 PMCID: PMC10769801 DOI: 10.1093/oncolo/oyad180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 05/25/2023] [Indexed: 07/02/2023] Open
Abstract
BACKGROUND Combination chemotherapy and immunotherapy regimens have significantly improved survival for patients with previously untreated advanced non-small cell lung cancer (NSCLC). Improvements in overall survival (OS) in two separate pembrolizumab trials have demonstrated survival improvements over chemotherapy alone, regardless of PD-L1 status. The optimal chemotherapy backbone for combination with immunotherapy is unknown. We hypothesized nab-paclitaxel may be a well-suited platinum partner to use in combination with checkpoint inhibitor therapy for both adenocarcinoma and squamous histology and conducted a phase I/II trial to assess the efficacy of this regimen in advanced NSCLC. METHODS Adult patients with previously untreated, stage IIIB/IV NSCLC (any histology) with an Eastern Cooperative Oncology Group performance status of 0-1, any PD-L1 expression, and no EGFR mutations or ALK translocations, received carboplatin area under the curve (AUC) 6 day 1, nab-paclitaxel 100 mg/m2 days 1, 8, 15, and pembrolizumab 200 mg day 1 q21 days for 4 cycles followed by maintenance pembrolizumab q3w. Co-primary endpoints were progression-free survival (PFS) and overall response rate (ORR). RESULTS Forty-six evaluable patients enrolled, 14 in phase I and 32 in phase II, from June 2015 to July 2018 with a median duration of follow-up of 35.4 months. Median time from enrollment to data lock was 42 months. In the ITT population, the ORR was 35%, median PFS was 5.6 months (95% CI, 4.6-8.2), and median OS was 15.4 months (CI, 12.4-28.1). There were no statistical differences in PFS or OS by PD-L1 status. The 2- and 3-year landmark OS rates were 33% and 24%, respectively. CONCLUSION Carboplatin, nab-paclitaxel, and pembrolizumab are a safe and effective regimen for patients with both squamous and nonsquamous NSCLC. Although this study did not meet the prespecified endpoints, the median and landmark OS results are consistent with durable benefit of this regimen as seen in phase III trials for first-line treatment of advanced NSCLC.
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Affiliation(s)
- Ryan D Gentzler
- Department of Medicine, Division of Hematology/Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA
| | - Nisha A Mohindra
- Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - Shadia I Jalal
- Department of Medicine, Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA
| | - Karen L Reckamp
- Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Richard D Hall
- Department of Medicine, Division of Hematology/Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA
| | - Nasser H Hanna
- Department of Medicine, Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA
| | - Young Kwang Chae
- Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - Marianna Koczywas
- Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Irene B Helenowski
- Department of Preventive Medicine, Northwestern University, Chicago, IL, USA
| | - Jyoti D Patel
- Department of Medicine, Division of Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
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10
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Al-Taie A, Sheta N. Clinically Approved Monoclonal Antibodies-based Immunotherapy: Association With Glycemic Control and Impact Role of Clinical Pharmacist for Cancer Patient Care. Clin Ther 2024; 46:e29-e44. [PMID: 37932154 DOI: 10.1016/j.clinthera.2023.10.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/17/2023] [Accepted: 10/13/2023] [Indexed: 11/08/2023]
Abstract
PURPOSE Compared with more conventional, nonspecific therapy options, such as radiotherapy and chemotherapy, monoclonal antibodies (mAbs) constitute a crucial approach of cancer treatment. Multiple autoimmune diseases have been observed during treatment with mAb medications, including autoimmune diabetes mellitus (DM). This study provides a narrative review of clinically approved mAbs in cancer treatment and focuses on the development of hyperglycemia and DM arising from using these therapies. Furthermore, it highlights the critical role of oncology clinical pharmacists in the management of autoimmune DM and patient care while using these medications in an oncology setting. METHODS An extensive literature search was conducted using various sources of electronic databases, such as Scopus, Embase, Web of Science, and PubMed, and search engines, such as Google Scholar, for studies on mAb classification, types, mechanisms of action, pharmacokinetic properties, current clinical applications, and the associated common adverse effects with significant recommendations for patient care in an oncology setting, along with focusing on the proposed mechanisms and clinical studies that reported the association of DM after the use of these therapies. FINDINGS There are 4 types (murine, chimeric, humanized, and human) and 3 classes (unconjugated, conjugated, and bispecific) of mAbs with several mechanisms of action that can destroy cancer cells, including preventing tumor cell survival cascades, inhibiting tumor growth by interfering with tumor angiogenesis, evading programmed cell death, and bypassing immune checkpoints. However, multiple endocrinopathies, autoimmune diseases, and complications were reported from the use of these medications, including the development of autoimmune DM and diabetic ketoacidosis. These autoimmune disorders were reported most with the use of immune checkpoint inhibitors, including inhibitors of the programmed cell death protein 1 (nivolumab and pembrolizumab), its ligand (atezolizumab, avelumab, and durvalumab), and cytotoxic T-lymphocyte-associated protein 4 (ipilimumab). IMPLICATIONS mAbs are considered important approaches for the treatment of many cancer types. However, a high incidence of hyperglycemia, type 1 DM, and diabetic ketoacidosis is observed with the use of these medications, particularly immune checkpoint inhibitors. It is important for oncologic clinical pharmacists to be involved in addressing these autoimmune disorders from the use of these immunotherapies via the provision of patient education, medication adherence support, close monitoring, and follow-up, which will lead to better health-related outcomes and improved patient quality of life.
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Affiliation(s)
- Anmar Al-Taie
- Clinical Pharmacy Department, Faculty of Pharmacy, Istinye University, Istanbul, Türkiye.
| | - Najat Sheta
- Clinical Pharmacy Department, Faculty of Pharmacy, Istinye University, Istanbul, Türkiye
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11
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Bhanderi H, Khalid F, Bodla ZH, Muhammad T, Du D, Meghal T. Autoimmune diabetes from pembrolizumab: A case report and review of literature. World J Clin Oncol 2023; 14:535-543. [PMID: 38059185 PMCID: PMC10696214 DOI: 10.5306/wjco.v14.i11.535] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/13/2023] [Accepted: 10/30/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Immunotherapy, specifically the use of checkpoint inhibitors such as pembrolizumab, has become an important tool in personalized cancer therapy. These inhibitors target proteins on T-cells that regulate the immune response against tumor cells. Pembrolizumab, which targets the programmed cell death 1 receptor on T-cells, has been approved for the treatment of metastatic melanoma and non-small cell lung cancer. However, it can also lead to immune-related side effects, including pneumonitis, colitis, thyroid abnormalities, and rare cases of type 1 diabetes. CASE SUMMARY The case presented involves an adult patient in 30s with breast cancer who developed hyperglycemia after receiving pembrolizumab treatment. The patient was diagnosed with diabetic ketoacidosis and further investigations were performed to evaluate for new-onset type 1 diabetes. The patient had a history of hypothyroidism and a family history of breast cancer. Treatment for diabetic ketoacidosis was initiated, and the patient was discharged for close follow-up with an endocrinologist. CONCLUSION This literature review highlights the occurrence of diabetic ketoacidosis and new-onset type 1 diabetes in patients receiving pembrolizumab treatment for different types of cancer. Overall, the article emphasizes the therapeutic benefits of immunotherapy in cancer treatment, particularly pembrolizumab, while also highlighting the potential side effect of immune-related diabetes that can occur in a small percentage of patients. Here we present a case where pembrolizumab lead to development of diabetes after a few cycles highlighting one of the rare yet a serious toxicity of the drug.
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Affiliation(s)
- Hardikkumar Bhanderi
- Department of Internal Medicine, Monmouth Medical Center, Long branch, NJ 07740, United States
| | - Farhan Khalid
- Department of Internal Medicine, Monmouth Medical Center, Long branch, NJ 07740, United States
| | - Zubair Hassan Bodla
- Department of Internal Medicine, University of Central Florida College of Medicine, Gainesville, FL 32303, United States
| | - Tayyeb Muhammad
- Department of Internal Medicine, Monmouth Medical Center, Long branch, NJ 07740, United States
| | - Doantrang Du
- Department of Internal Medicine, Monmouth Medical Center, Long branch, NJ 07740, United States
| | - Trishala Meghal
- Department of Hematology-Oncology, Monmouth Medical Center, Long Branch, NJ 07740, United States
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12
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Daetwyler E, Zippelius A, Danioth S, Donath MY, Gut L. Nivolumab-induced diabetes mellitus-a case report with literature review of the treatment options. Front Immunol 2023; 14:1248919. [PMID: 37965350 PMCID: PMC10640970 DOI: 10.3389/fimmu.2023.1248919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 10/10/2023] [Indexed: 11/16/2023] Open
Abstract
Background Immune checkpoint inhibitor (ICI) treatment has become important for treating various cancer types, including metastatic renal cell carcinoma. However, ICI treatment can lead to endocrine immune-related adverse events (irAEs) by overstimulating the patient's immune system. Here, we report a rare case of a new onset of diabetes mellitus (DM), caused by nivolumab, and we discuss the feasible treatment options with a focus on TNF antagonism. Case presentation A 50-year-old man was diagnosed with metastatic renal cell carcinoma. Due to systemic progression, a combined immunotherapy with ipilimumab and nivolumab was initiated, according to the current study protocol (SAKK 07/17). The administration of ipilimumab was stopped after 10 months, due to partial response as seen in the computer tomography (CT), and nivolumab was continued as monotherapy. Fourteen months after the start of the treatment, the patient was admitted to the emergency department with lethargy, vomiting, blurred vision, polydipsia, and polyuria. The diagnosis of DM with diabetic ketoacidosis was established, although autoantibodies to β-cells were not detectable. Intravenous fluids and insulin infusion treatment were immediately initiated with switching to a subcutaneous administration after 1 day. In addition, the patient received an infusion of the TNF inhibitor infliximab 4 days and 2 weeks after the initial diagnosis of DM. However, the C-peptide values remained low, indicating a sustained insulin deficiency, and the patient remained on basal bolus insulin treatment. Two months later, nivolumab treatment was restarted without destabilization of the diabetic situation. Conclusions In contrast to the treatment of other irAEs, the administration of corticosteroids is not recommended in ICI-induced DM. The options for further treatment are mainly based on the low numbers of case series and case reports. In our case, the administration of infliximab-in an attempt to salvage the function of β-cells-was not successful, and this is in contrast to some previous reports. This apparent discrepancy may be explained by the absence of insulin resistance in our case. There is so far no evidence for immunosuppressive treatment in this situation. Prompt recognition and immediate start of insulin treatment are most important in its management.
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Affiliation(s)
- Eveline Daetwyler
- Department of Medical Oncology, University Hospital Basel, Basel, Switzerland
| | - Alfred Zippelius
- Department of Medical Oncology, University Hospital Basel, Basel, Switzerland
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Simona Danioth
- Clinic for Endocrinology, Diabetes & Metabolism, Luzern Cantonal Hospital, Luzern, Switzerland
| | - Marc Y. Donath
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Clinic for Endocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland
| | - Lara Gut
- Clinic for Endocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland
- Clinic for Endocrinology & Diabetes, Medical University Clinic Baselland, Liestal, Switzerland
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Wen YP, Xiao HW, Yin JH, Guo HR, Shan MJ, Shen LP, Liu LS. Simultaneous development of pneumonitis and autoimmune diabetes secondary to immune checkpoint inhibitor treatment with durvalumab in an advanced small cell lung cancer patient: A case report. Medicine (Baltimore) 2022; 101:e32076. [PMID: 36482651 PMCID: PMC9726362 DOI: 10.1097/md.0000000000032076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
RATIONALE Immune checkpoint inhibitors (ICIs) have been widely used in the treatment of various types of cancers worldwide, which is the most significant breakthrough in cancer therapy in recent years. Despite their excellent benefits in anti-tumor efficacy, a subset of patients will experience various autoimmune toxicities, termed as immune-related adverse events (irAEs), which can affect almost any organ systems, but related to the pulmonary and pancreatic islets simultaneously has rarely been reported and discussed. PATIENT CONCERNS In this report, we describe a rare case of a 65-year-old man patient with advanced small cell lung cancer (SCLC) who suffered general fatigue, dry cough, chest tightness, shortness of breath and polyuria-polydipsia syndrome after the eighth cycle treatment with programmed cell death ligand-1 (PD-L1) inhibitor durvalumab. DIAGNOSES According to the results of laboratory tests, chest computed tomography and multidisciplinary discussion, the patient was eventually diagnosed with ICI-related pneumonitis and autoimmune diabetes mellitus. INTERVENTIONS Multiple daily subcutaneous insulin injections, empirical anti-infection and immunosuppression treatment with corticosteroids were performed. OUTCOMES After the cessation of durvalumab and comprehensive treatment, the patient's respiratory condition was relieved significantly and his blood glucose was well controlled with insulin therapy. LESSONS With the widespread use of ICIs, there will be more patients developing these rare but severe irAEs in clinical practice, which should attract great attention of both clinicians and patients.
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Affiliation(s)
- Yan-Ping Wen
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hai-Wei Xiao
- Department of Traditional Chinese Medicine, Shenshan Medical Center, Memorial Hospital of Sun Yat-sen University, Shanwei, Guangdong Province, China
| | - Ju-Hua Yin
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hui-Ru Guo
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Meng-Jun Shan
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li-Ping Shen
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ling-Shuang Liu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- * Correspondence: Ling-Shuang Liu, Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, No. 725 Wanping South Road, Xuhui District, Shanghai 200032, China (e-mail: )
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14
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Liu J, Shi Y, Liu X, Zhang D, Zhang H, Chen M, Xu Y, Zhao J, Zhong W, Wang M. Clinical characteristics and outcomes of immune checkpoint inhibitor-induced diabetes mellitus. Transl Oncol 2022; 24:101473. [PMID: 35905639 PMCID: PMC9334308 DOI: 10.1016/j.tranon.2022.101473] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/06/2022] [Accepted: 06/26/2022] [Indexed: 11/07/2022] Open
Abstract
This article summarized a total of 172 published cases of immune checkpoint inhibitor (ICI)-induced diabetes mellitus (DM). Found that glutamic acid decarboxylase antibodies positivity is related to an earlier onset of ICI-induced diabetes and a higher frequency of diabetic ketoacidosis development. Presented a case of ICI-induced DM following obvious lipase and amylase elevation and discussed possible relationship between ICI-associated injuries to pancreatic exocrine function and endocrine function. Objective To better understand immune checkpoint inhibitor (ICI)-induced diabetes mellitus (DM) in cancer patients. Design and method We present a case of ICI-induced diabetic ketoacidosis (DKA) and conduct a systematic review of the PubMed and Web of Science databases up to September 2021 to identify all published cases of ICI-induced diabetes. Results In addition to our case, a total of 171 published cases were identified during the literature search. Summary and statistical analyzes were conducted for all 172 cases. The median onset time from ICI initiation to DM diagnosis was 12 weeks (range: 0–122). DKA was present in 67.4% (116/172) of the cases, and low C-peptide levels were detected in 91.8% (123/134), indicating an acute onset of diabetes. Patients with positive glutamic acid decarboxylase antibodies (GADA) had an earlier onset of ICI-induced diabetes (median time 7 weeks vs. 16 weeks for GADA-negative patients, p < 0.001) and a higher frequency of DKA development (82.8 vs. 62.1%, p = 0.006). All but two patients developed insulin-dependent diabetes permanently. Immunotherapy rechallenge was reported in 53 cases after glycemia was well controlled. Conclusion ICI-induced DM is a serious adverse event that often presents with life-threatening ketoacidosis. GADA positivity is related to an earlier onset of ICI-induced diabetes and a higher frequency of DKA development. Close monitoring of glucose levels is needed in patients receiving ICI treatment. ICI-induced DM is usually insulin-dependent since damage to β cells is irreversible. On the premise of well-controlled glycemia, immunotherapy rechallenge is feasible.
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Affiliation(s)
- Jia Liu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuequan Shi
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoyan Liu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dongming Zhang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haoran Zhang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Minjiang Chen
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Xu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Zhao
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Zhong
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mengzhao Wang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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15
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Pachpande V, Mullangi S, Lekkala MR, Patel A. New-Onset Autoimmune Diabetes Mellitus Presenting As Diabetic Ketoacidosis in Association With Pembrolizumab Therapy and Long Term Follow-Up: Case Report. Cureus 2022; 14:e24479. [PMID: 35651416 PMCID: PMC9132754 DOI: 10.7759/cureus.24479] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2022] [Indexed: 11/22/2022] Open
Abstract
Pembrolizumab, an immune checkpoint inhibitor (ICI) that acts against receptor programmed cell death-1 (PD-1), is currently being used in the treatment of a variety of cancers. As PD-1 is also present on other non-malignant tissues, this results in side effects involving a multitude of organ systems termed immune-related adverse effects (irAEs). Programmed cell death-1 is expressed on the beta cells of islets of the pancreas, and their destruction can result in hyperglycemia and the onset of new diabetes mellitus (DM). Thus, the anti-PD1 action of pembrolizumab can lead to autoimmune-related DM. We present a case of a 62-year-old male who developed new-onset DM after 12 cycles of pembrolizumab with a severe presentation in the form of diabetic ketoacidosis (DKA) and ICU stay. Our case underscores the importance of physician awareness, frequent lab monitoring and patient education about this rare but potentially fatal irAE of ICI. It also strengthens existing data in literature suggesting the association of irAEs with improved efficacy of ICI therapy.
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16
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Shen L, Li J, Liu Q, Das M, Song W, Zhang X, Tiruthani K, Dorosheva O, Hu H, Lai SK, Liu R, Huang L. Nano-trapping CXCL13 reduces regulatory B cells in tumor microenvironment and inhibits tumor growth. J Control Release 2022; 343:303-313. [DOI: 10.1016/j.jconrel.2022.01.039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 01/19/2022] [Accepted: 01/24/2022] [Indexed: 01/11/2023]
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17
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Charles S, Poullard A. Occurrence of Type 1 Diabetes in A Patient Enrolled in An Immunotherapy Combination Phase 1 Clinical Trial: A Case Study. Asia Pac J Oncol Nurs 2021; 8:737-739. [PMID: 34790859 PMCID: PMC8522589 DOI: 10.4103/apjon.apjon-2122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 03/21/2021] [Indexed: 11/24/2022] Open
Abstract
Advances in cancer immunotherapy treatments have shown promising results in patients with metastatic malignancy who have been refractory to prior treatments. Immune checkpoint inhibitors such as pembrolizumab in combination with other systemic agents may unleash immune-related adverse events (irAEs). Immunotherapy-induced Type 1 diabetes is rare; however, if left undiagnosed, it may cause life-threatening metabolic endocrinopathies. Advanced practice registered nurses are in a unique position to recognize and identify this irAE and in doing so can provide pathways for early diagnosis and treatments, thus leading to improved clinical and patient outcomes.
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Affiliation(s)
- Sheena Charles
- Department of Investigational Cancer Therapeutics (A Phase 1 Program), University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anna Poullard
- Department of Investigational Cancer Therapeutics (A Phase 1 Program), University of Texas MD Anderson Cancer Center, Houston, TX, USA
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18
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Fujiwara N, Watanabe M, Katayama A, Noda Y, Eguchi J, Kataoka H, Kagawa S, Wada J. Longitudinal observation of insulin secretory ability before and after the onset of immune checkpoint inhibitor-induced diabetes mellitus: A report of two cases. Clin Case Rep 2021; 9:e04574. [PMID: 34522382 PMCID: PMC8424178 DOI: 10.1002/ccr3.4574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 05/31/2021] [Accepted: 06/16/2021] [Indexed: 01/15/2023] Open
Abstract
Immune checkpoint inhibitor-induced diabetes mellitus is a rare immune-related adverse event. This report illustrates clinical data and insulin secretory ability before and after the onset of immune checkpoint inhibitor-induced diabetes.
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Affiliation(s)
- Noriko Fujiwara
- Department of Nephrology, Rheumatology, Endocrinology and MetabolismDentistry and Pharmaceutical SciencesOkayama University Graduate School of MedicineOkayamaJapan
- Division of Endocrinology and MetabolismHiroshima Red Cross Hospital and Atomic‐bomb Survivors HospitalHiroshimaJapan
| | - Mayu Watanabe
- Department of Primary Care and Medical EducationDentistry and Pharmaceutical SciencesOkayama University Graduate School of MedicineOkayamaJapan
| | | | - Yohei Noda
- Department of Otolaryngology‐Head and Neck SurgeryDentistry and Pharmaceutical SciencesOkayama University Graduate School of MedicineOkayamaJapan
| | - Jun Eguchi
- Department of Nephrology, Rheumatology, Endocrinology and MetabolismDentistry and Pharmaceutical SciencesOkayama University Graduate School of MedicineOkayamaJapan
| | - Hitomi Kataoka
- Department of Primary Care and Medical EducationDentistry and Pharmaceutical SciencesOkayama University Graduate School of MedicineOkayamaJapan
| | - Shunsuke Kagawa
- Minimally Invasive Therapy CenterOkayama University HospitalOkayamaJapan
| | - Jun Wada
- Department of Nephrology, Rheumatology, Endocrinology and MetabolismDentistry and Pharmaceutical SciencesOkayama University Graduate School of MedicineOkayamaJapan
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19
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Lee S, Tse G. A Patient with Atezolizumab-Induced Autoimmune Diabetes Mellitus Presenting with Diabetic Ketoacidosis. CARDIOVASCULAR INNOVATIONS AND APPLICATIONS 2021. [DOI: 10.15212/cvia.2021.0007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Background: Atezolizumab, an immune checkpoint inhibitor, is a humanized monoclonal, anti-programmed death ligand 1 (PD-L1) antibody used for the treatment of metastatic urothelial carcinoma that has progressed after chemotherapy.Case Presentation: We describe a patient
with a known history of urothelial carcinoma who presented with diabetic ketoacidosis 6 weeks following his second cycle of atezolizumab. His serum lactate level was slightly elevated (2 mM) and his β-hydroxybutyrate level was elevated (3.9 mM). High anion gap metabolic acidosis secondary
to diabetic ketoacidosis was diagnosed. Subsequent testing demonstrated hemoglobin A1c level of 9.9%, positivity for anti-glutamic acid decarboxylase antibody (0.03 nM, reference range <0.02 nM), and suppressed C-peptide level (0.1 μg/L, reference range 0.9‐7.1 μg/L)
in the absence of detectable anti-islet antigen 2 (IA-2) or anti-insulin antibodies. His initial management included cessation of atezolizumab treatment, intravenous sodium chloride administration, and insulin pump infusion, after which metabolic acidosis gradually resolved. The insulin pump
was subsequently switched to Protaphane at 18 units before breakfast and 8 units before dinner, together with metformin at 1000 mg twice daily. Four weeks later his medication was changed to human isophane insulin plus neutral insulin (70%/30%; Mixtard 30 HM; 26 units/4 units). Linagliptin
at 5 mg was added 1 month later. His hemoglobin A1c level declined to 8.1% 1 year later.Conclusions: PD-L1 inhibitors can induce type 1 diabetes, and patients can present with diabetic ketoacidosis. Blood glucose levels should be regularly monitored in patients who are
prescribed these medications.
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Affiliation(s)
- Sharen Lee
- Cardiovascular Analytics Group, Laboratory of Cardiovascular Physiology, Hong Kong, HKG, China
| | - Gary Tse
- Cardiovascular Analytics Group, Laboratory of Cardiovascular Physiology, Hong Kong, HKG, China
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20
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Yim C, Mansell K, Hussein N, Arnason T. Current cancer therapies and their influence on glucose control. World J Diabetes 2021; 12:1010-1025. [PMID: 34326951 PMCID: PMC8311484 DOI: 10.4239/wjd.v12.i7.1010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/11/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes. These groups of medications were selected due to their significant association with new onset hyperglycemia, or of potentially severe clinical consequences when present. These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments, and the antimetabolite class of 5-fluorouracil-related drugs. Both of these classes have been in use in cancer therapy since the 1950s. Also considered are the phosphatidyl inositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-inhibitors that provide cancer response advantages by disrupting cell growth, proliferation and survival signaling pathways, and have been in clinical use as early as 2007. The final class to be reviewed are the monoclonal antibodies selected to function as immune checkpoint inhibitors (ICIs). These were first used in 2011 for advanced melanoma and are rapidly becoming widely utilized in many solid tumors. For each drug class, the literature has been reviewed to answer relevant questions about these medications related specifically to the characteristics of the hyperglycemia that develops with use. The incidence of new glucose elevations in euglycemic individuals, as well as glycemic changes in those with established diabetes has been considered, as has the expected onset of hyperglycemia from their first use. This comparison emphasizes that some classes exhibit very immediate impacts on glucose levels, whereas other classes can have lengthy delays of up to 1 year. A comparison of the spectrum of severity of hyperglycemic consequences stresses that the appearance of diabetic ketoacidosis is rare for all classes except for the ICIs. There are distinct differences in the reversibility of glucose elevations after treatment is stopped, as the mTOR inhibitors and ICI classes have persistent hyperglycemia long term. These four highlighted drug categories differ in their underlying mechanisms driving hyperglycemia, with clinical presentations ranging from potent yet transient insulin resistant states [type 2 diabetes mellitus (T2DM) -like] to rare permanent insulin-deficient causes of hyperglycemia. Knowledge of the relative incidence of new onset hyperglycemia and the underlying causes are critical to appreciate how and when to best screen and treat patients taking any of these cancer drug therapies.
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Affiliation(s)
- Carly Yim
- Department of Medicine, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Kerry Mansell
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
| | - Nassrein Hussein
- Department of Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Terra Arnason
- Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
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21
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Lo Preiato V, Salvagni S, Ricci C, Ardizzoni A, Pagotto U, Pelusi C. Diabetes mellitus induced by immune checkpoint inhibitors: type 1 diabetes variant or new clinical entity? Review of the literature. Rev Endocr Metab Disord 2021; 22:337-349. [PMID: 33409866 DOI: 10.1007/s11154-020-09618-w] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/24/2020] [Indexed: 12/16/2022]
Abstract
Immune Check-Point Inhibitors (CPIs) have improved long-term patients' outcomes in several advanced cancers. Diabetes mellitus induced by CPIs (CPI-DM) is considered the second most frequent endocrine CPIs' side effects with a variable prevalence up to 2%. The aim of our study was to identify CPI-DM characteristics and differences from the classical form of diabetes. Therefore, we conducted a structured Pubmed® search collecting publications dated from January 2015 to December 2019. A total of 642 citations were identified and 121 publications met our study criteria. We analyzed 200 case reports, including our 3 cases under publication. The majority of CPI-DM occurred with anti-Programmed cell Death-1 in monotherapy or in combination, although few cases with Programmed cell Death Ligand-1 and Cytotoxic T Lymphocyte Antigen 4 were reported. Generally, CPI-DM arose early (an average of 9 weeks after CPIs starting), but also after the end of CPIs treatment. In all patients, CPI-DM has an acute onset and in 67.5% of cases diabetic ketoacidosis occurs. C-peptide levels were usually and permanently compromised, requiring lifelong insulin therapy. Moreover, autoimmunity and genetic profile was not always helpful. In particular, anti-glutamic acid decarboxylase (anti-GAD) antibodies and Human Leukocyte Antigen (HLA) DR4 were present in only 43.0% and 51.3% of cases respectively. In 51.0% of subjects a mild exocrine impairment coexisted. In short, though CPI-DM has similarities to type 1 diabetes mellitus, it represents a new, largely unknown, clinical entity. In addition, as CPI-DM is a relative frequent side-effect under CPI, a close monitoring of the glucose levels and early signs and symptoms of diabetes in patients affected by neoplasm is recommended.
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Affiliation(s)
- V Lo Preiato
- Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - S Salvagni
- Division of Medical Oncology, Department of Experimental Diagnostic and Speciality Medicine (DIMES), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Bologna, Italy
| | - C Ricci
- Surgical Department, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, Sant'Orsola Hospital, Bologna, Italy
| | - A Ardizzoni
- Division of Medical Oncology, Department of Experimental Diagnostic and Speciality Medicine (DIMES), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Bologna, Italy
| | - U Pagotto
- Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy.
| | - C Pelusi
- Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy
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22
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Husain B, Kirchberger MC, Erdmann M, Schüpferling S, Abolhassani AR, Fröhlich W, Berking C, Heinzerling L. Inflammatory markers in autoimmunity induced by checkpoint inhibitors. J Cancer Res Clin Oncol 2021; 147:1623-1630. [PMID: 33837821 PMCID: PMC8076116 DOI: 10.1007/s00432-021-03550-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 02/04/2021] [Indexed: 12/11/2022]
Abstract
PURPOSE Immune checkpoint inhibitors (ICI) are highly effective in several cancer entities, but also invoke a variety of immune-related adverse events (irAE). These are mostly reversible, but can be life-threatening or even fatal. Currently, the pathogenesis is not fully understood, but crucial for effective treatment. Prediction and early detection of irAE could be facilitated and treatment optimized if relevant biomarkers and effector mechanisms were better characterized. METHODS This study included a total of 45 irAE in patients with metastatic melanoma who were treated with ICI. All patients underwent a complete work-up with exclusion of other causes. Longitudinal blood samples were analyzed for a panel of soluble markers and compared to baseline and to patients who did not experience any irAE. Measurements included LDH, interleukin (IL)-6, IL-1β, IL-17, C-reactive protein (CRP) and tumor necrosis factor (TNF)-alpha as well as tumor markers S100 and melanoma inhibitory activity (MIA). RESULTS During the early onset of irAE increases in serum IL-6 (from mean 24.4 pg/ml at baseline to 51.0 pg/ml; p = 0.003) and CRP (from mean 7.0 mg/l at baseline to 17.7 mg/l; p = 0.001) and a decrease in MIA (from mean 5.4 pg/ml at baseline to 4.8 pg/ml; p = 0.035) were detected. No changes in IL-17 were noted. These effects were observed for irAE of different organ systems. CONCLUSION Increases of a combination of IL-6 and CRP serum levels can be used for the early detection of irAE and tailored management. Interestingly, changes in MIA serum levels also correlate with irAE onset.
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Affiliation(s)
- Beate Husain
- Department of Dermatology, Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany
- Friedrich-Alexander University Erlangen-Nuremberg, 91054, Erlangen, Germany
| | - Michael Constantin Kirchberger
- Friedrich-Alexander University Erlangen-Nuremberg, 91054, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054, Erlangen, Germany
- Deutsches Zentrum Für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, 91054, Erlangen, Germany
| | - Michael Erdmann
- Department of Dermatology, Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054, Erlangen, Germany
- Deutsches Zentrum Für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, 91054, Erlangen, Germany
| | - Sabine Schüpferling
- Department of Dermatology, Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054, Erlangen, Germany
- Deutsches Zentrum Für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, 91054, Erlangen, Germany
| | | | - Waltraud Fröhlich
- Department of Dermatology, Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054, Erlangen, Germany
- Deutsches Zentrum Für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, 91054, Erlangen, Germany
| | - Carola Berking
- Department of Dermatology, Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054, Erlangen, Germany
- Deutsches Zentrum Für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, 91054, Erlangen, Germany
| | - Lucie Heinzerling
- Department of Dermatology, Universitätsklinikum Erlangen, Ulmenweg 18, 91054, Erlangen, Germany.
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054, Erlangen, Germany.
- Deutsches Zentrum Für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, 91054, Erlangen, Germany.
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Kyriacou A, Melson E, Chen W, Kempegowda P. Is immune checkpoint inhibitor-associated diabetes the same as fulminant type 1 diabetes mellitus? Clin Med (Lond) 2021; 20:417-423. [PMID: 32675150 DOI: 10.7861/clinmed.2020-0054] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Pembrolizumab is an anti-cancer drug that targets programmed cell death protein-1 (PD-1) receptors on lymphocytes resulting in their activation against tumour cells. PD-1 receptors are also interspersed in endocrine organs and pembrolizumab use has long been associated with hypophysitis and thyroiditis. Since the introduction of immune checkpoint inhibitors (ICI), several cases of fulminant type 1 diabetes mellitus (FT1DM) have been reported. However, it is unclear if FT1DM and ICI-induced diabetes are the same pathology. We review the existing literature of ICI-induced diabetes to investigate its nature and to what extent it represents type 1A diabetes and/or FT1DM (type 1B diabetes) using an example case. Our review showed that ICI-induced diabetes may be a different entity to FT1DM. Furthermore, there is limited evidence for the management of ICI-induced T1DM. Further research into its pathophysiology will improve management and possibly prevent this burdensome complication.
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Affiliation(s)
- Angelos Kyriacou
- Centre of Endocrinology, Diabetes and Metabolism, Limassol, Cyprus
| | - Eka Melson
- Institute of Metabolism and Systems Research, Birmingham, UK and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | | | - Punith Kempegowda
- Institute of Metabolism and Systems Research, Birmingham, UK and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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24
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Goyal I, Pandey MR, Sharma R, Chaudhuri A, Dandona P. The side effects of immune checkpoint inhibitor therapy on the endocrine system. Indian J Med Res 2021; 154:559-570. [PMID: 35435341 PMCID: PMC9205006 DOI: 10.4103/ijmr.ijmr_313_19] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) are a relatively newer class of drugs approved for the treatment of malignancies such as melanoma, renal, bladder and lung cancer. Immune-related adverse events (IrAEs) involving the endocrine system are a common side effect of these drugs. The spectrum of endocrine adverse events varies by the drug class. Cytotoxic T-lymphocyte–associated antigen-4 inhibitors commonly cause hypophysitis/hypopituitarism, whereas the incidence of thyroid disease is higher with programmed cell death (PD)-1/ ligand (PD-L) protein 1 inhibitors. The focus of this review is to describe the individual endocrinopathies with their possible mechanisms, signs and symptoms, clinical assessment and disease management. Multiple mechanisms of IrAEs have been described in literature including type II/IV hypersensitivity reactions and development of autoantibodies. Patients with pre-existing autoimmune endocrine diseases can have disease exacerbation following ICI therapy rather than de novo IrAEs. Most of the endocrinopathies are relatively mild, and timely hormone replacement therapy allows continuation of ICIs. However, involvement of the pituitary–adrenal axis could be life-threatening if not recognized. Corticosteroids are helpful when the pituitary–adrenal axis is involved. In cases of severe endocrine toxicity (grade 3/4), ICIs should be temporarily discontinued and can be restarted after adequate hormonal therapy. Endocrinologists and general internists need to be vigilant and maintain a high degree of awareness for these adverse events.
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Affiliation(s)
- Itivrita Goyal
- Department of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo, Buffalo, NY, USA
| | - Manu Raj Pandey
- Department of Hematology & Oncology, State University of New York at Buffalo; Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Rajeev Sharma
- Department of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo; Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Ajay Chaudhuri
- Department of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo, Buffalo, NY, USA
| | - Paresh Dandona
- Department of Endocrinology, Diabetes & Metabolism, State University of New York at Buffalo, Buffalo, NY, USA
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25
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Liu Y, Zhang H, Zhou L, Li W, Yang L, Li W, Li K, Liu X. Immunotherapy-Associated Pancreatic Adverse Events: Current Understanding of Their Mechanism, Diagnosis, and Management. Front Oncol 2021; 11:627612. [PMID: 33732647 PMCID: PMC7959713 DOI: 10.3389/fonc.2021.627612] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/18/2021] [Indexed: 02/05/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 (PD-1) and its ligand PD-L1 and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibodies, are involved in T cell-mediated immune response augmentation and promote anti-tumor immunity. Cancer patients treated with combination of immunotherapy, chemotherapy, radiotherapy, and targeted therapy exhibit superior clinical outcomes and tolerance compared with patients treated with monotherapies. However, immutherapy is associated with several concomitant immune-related adverse events (irAEs). For instance, IrAEs interferes with function of gastrointestinal tract, endocrine, dermatological, nervous system and musculoskeletal systems. ICIs-associated pancreatic injury might causes decrease in endocrine and exocrine pancreatic function, resulting in metabolic and nutritional disorders. Clinicians who administer immune checkpoint inhibitors to cancer patients are diagnosed with hyperglycemia, abdominal pain and steatorrhea. Currently, the precise mechanism of ICIs-associated pancreatic injury has not been fully explored. This paper summarizes incidence, diagnosis, clinical characteristics, potential mechanisms, and treatment management patterns of ICIs-associated pancreatic AEs based on previous studies. In addition, possible management approaches of these adverse effects are presented in this paper. in the findings summarized in this paper lay a basis for management of ICIs-associated pancreatic AEs and expanding future immunotherapy applications.
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Affiliation(s)
- Ya Liu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Zhang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Li Zhou
- Core Facilities, West China Hospital, Sichuan University, Chengdu, China
| | - Weichun Li
- CAAC Academy, Civil Aviation Flight University of China, Guanghan, China
| | - Le Yang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Wen Li
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Kezhou Li
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Xubao Liu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
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Paschou SA, Stefanaki K, Psaltopoulou T, Liontos M, Koutsoukos K, Zagouri F, Lambrinoudaki I, Dimopoulos MA. How we treat endocrine complications of immune checkpoint inhibitors. ESMO Open 2021; 6:100011. [PMID: 33399077 PMCID: PMC7807832 DOI: 10.1016/j.esmoop.2020.100011] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/06/2020] [Accepted: 11/10/2020] [Indexed: 12/18/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) are antibodies that target certain immune checkpoints (ICs), such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), and have emerged as a powerful new tool for oncologists. As these immune checkpoints are crucial for immunological self-tolerance, such therapies can trigger autoimmune adverse effects. Endocrine complications are among the most common, including hypophysitis, thyroid dysfunction, diabetes mellitus and primary adrenal insufficiency, while autoimmune polyendocrine syndrome type 2 (APS-2) may also present. The aim of this article is to critically appraise the literature and present (i) the biological role and function of the main ICs, (ii) the use of ICIs in the treatment of various cancer types, (iii) the endocrine complications of cancer immunotherapy with ICIs and (iv) practical recommendations for screening and management of patients with such endocrinopathies in everyday clinical practice.
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Affiliation(s)
- S A Paschou
- Division of Endocrinology, Diabetes and Metabolism, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - K Stefanaki
- Division of Endocrinology, Diabetes and Metabolism, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - T Psaltopoulou
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - M Liontos
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - K Koutsoukos
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - F Zagouri
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - I Lambrinoudaki
- Second Department of Obstetrics and Gynecology, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - M-A Dimopoulos
- Division of Hematology and Oncology, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
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Zhang AL, Wang F, Chang LS, McDonnell ME, Min L. Coexistence of Immune Checkpoint Inhibitor-Induced Autoimmune Diabetes and Pancreatitis. Front Endocrinol (Lausanne) 2021; 12:620522. [PMID: 33927691 PMCID: PMC8076788 DOI: 10.3389/fendo.2021.620522] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 03/16/2021] [Indexed: 02/05/2023] Open
Abstract
Autoimmune diabetes is a rare but severe endocrine toxicity induced by immune checkpoint inhibitor (ICI) treatment. It is unclear if ICI causes selective islet toxicity or non-selective pancreas toxicity. We analyzed 11 patients treated with ICI who developed ICI-related autoimmune diabetes. Eight patients had lipase and/or amylase tested on the same day of diagnosis of autoimmune diabetes. Among them, 75% (6/8) had normal lipase and 100% (6/6) had normal amylase. There was no correlation between glucose level at onset and biochemical pancreatitis. We characterized the clinical features of ICI-induced autoimmune diabetes. Fifty-five percent (6/11) of patients tested positive for GAD65 autoantibodies, and 55% (6/11) developed diabetic ketoacidosis at manifestation of hyperglycemia. In all 11 patients, C-peptide levels were low in the presence of hyperglycemia. ICI-induced thyroiditis was found in 64% (7/11), of which 36% (4/11) were newly diagnosed with thyroiditis while the remaining 27% (3/11) had pre-existing hypothyroidism followed by ICI-induced thyroiditis. Additionally, 27% (3/11), developed ICI-induced hypophysitis. Thyroiditis and autoimmune diabetes coexisted in all patients with ICI-induced hypophysitis. The median time from ICI treatment to the onset of autoimmune diabetes was 11 weeks. Our data suggest that few patients had coexistent ICI-induced autoimmune diabetes and pancreatitis, suggesting ICI mainly caused selective islet toxicity.
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Zhai Y, Ye X, Hu F, Xu J, Guo X, Zhou X, Zheng Y, Zhao X, Xu X, Cao Y, He J. Metabolic and Nutritional Disorders Following the Administration of Immune Checkpoint Inhibitors: A Pharmacovigilance Study. Front Endocrinol (Lausanne) 2021; 12:809063. [PMID: 35145482 PMCID: PMC8821653 DOI: 10.3389/fendo.2021.809063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 12/28/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Although several metabolic and nutritional disorders (MNDs) have been reported in the recipients of immune checkpoint inhibitors (ICIs), these events have not been fully captured and comprehensively characterized in real-world population. OBJECTIVES To provide complete metabolic and nutritional toxicity profiles after ICIs (single and combined) initiation through an integrated big database. METHODS Reporting odds ratios (ROR) and information component (IC) based on statistical shrinkage transformation were utilized to perform disproportionality analysis using the US Food and Drug Administration Adverse Events Reporting System. Both ROR and IC were used to calculate disproportionality when compared with the whole database, but only ROR was used when comparison was made for different ICI strategies. Only when both the lower limits of 95% confidence intervals (CIs) for ROR (ROR025) and IC (IC025) exceeded specified threshold values (1 and 0, respectively) was regarded as a signal. RESULTS A total of 29,294,335 records were involved and 8,662 records were for MNDs in patients exposed to ICIs. Statistically significant association was detected between ICIs use and total MNDs (IC025/ROR025 = 1.06/2.19). For monotherapy, three ICI monotherapies (anti-PD-1, anti-PDL-1, and anti-CTLA-4) were all disproportionately associated with MNDs. Statistically significant differences in reporting frequencies also emerged when comparing anti-PD-1 with anti-PD-L1/anti-CTLA-4 monotherapy, with RORs of 1.11 (95%CI 1.01-1.21), and 1.35 (95%CI 1.23-1.48), respectively. Notably, combination therapy was associated with a higher reporting frequency of theses toxicities compared to monotherapy with a ROR of 1.56 (95%CI 1.48-1.64). Additionally, disproportionality analysis at High-level Group Term level highlighted eight broad entities of MNDs. Further disproportionality analysis at Preferred Term level indicated a wide range and varied strength of signals. For ICI monotherapy, nivolumab and pembrolizumab showed the broadest spectrum of MNDs. For combination therapy, a variety of signals were detected for nivolumab + ipilimumab therapy even comparable to two PD-1 monotherapies. CONCLUSION Metabolic and nutritional complications could be provoked by ICI monotherapy (especially anti-PD-1) and further reinforced by combination therapy. Clinicians and patients should be informed about these potential risks that might be encountered in real-world practice. Aforehand education and regular monitoring of related biochemical parameters (calcium, sodium, potassium, protein) are recommended to ensure better cancer survivorship.
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Affiliation(s)
- Yinghong Zhai
- Tongji University School of Medicine, Shanghai, China
| | - Xiaofei Ye
- Department of Health Statistics, Second Military Medical University, Shanghai, China
| | - Fangyuan Hu
- Department of Health Statistics, Second Military Medical University, Shanghai, China
- Department of Medical Service, Naval Hospital of Eastern Theater Zhoushan, Zhejiang, China
| | - Jinfang Xu
- Department of Health Statistics, Second Military Medical University, Shanghai, China
| | - Xiaojing Guo
- Department of Health Statistics, Second Military Medical University, Shanghai, China
| | - Xiang Zhou
- Tongji University School of Medicine, Shanghai, China
| | - Yi Zheng
- Department of Health Statistics, Second Military Medical University, Shanghai, China
| | - Xinxin Zhao
- Tongji University School of Medicine, Shanghai, China
| | - Xiao Xu
- Tongji University School of Medicine, Shanghai, China
| | - Yang Cao
- Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Jia He
- Tongji University School of Medicine, Shanghai, China
- Department of Health Statistics, Second Military Medical University, Shanghai, China
- *Correspondence: Jia He,
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29
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Wu L, Tsang VHM, Sasson SC, Menzies AM, Carlino MS, Brown DA, Clifton-Bligh R, Gunton JE. Unravelling Checkpoint Inhibitor Associated Autoimmune Diabetes: From Bench to Bedside. Front Endocrinol (Lausanne) 2021; 12:764138. [PMID: 34803927 PMCID: PMC8603930 DOI: 10.3389/fendo.2021.764138] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 09/30/2021] [Indexed: 12/14/2022] Open
Abstract
Immune checkpoint inhibitors have transformed the landscape of oncological therapy, but at the price of a new array of immune related adverse events. Among these is β-cell failure, leading to checkpoint inhibitor-related autoimmune diabetes (CIADM) which entails substantial long-term morbidity. As our understanding of this novel disease grows, parallels and differences between CIADM and classic type 1 diabetes (T1D) may provide insights into the development of diabetes and identify novel potential therapeutic strategies. In this review, we outline the knowledge across the disciplines of endocrinology, oncology and immunology regarding the pathogenesis of CIADM and identify possible management strategies.
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Affiliation(s)
- Linda Wu
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
- Department of Endocrinology, Westmead Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- *Correspondence: Linda Wu,
| | - Venessa H. M. Tsang
- Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Sarah C. Sasson
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Department of Immunology, Westmead Hospital, Sydney, NSW, Australia
- NSW Health Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Sydney, NSW, Australia
| | - Alexander M. Menzies
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW, Australia
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
| | - Matteo S. Carlino
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Department of Medical Oncology, Westmead Hospital, Sydney, NSW, Australia
| | - David A. Brown
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Department of Immunology, Westmead Hospital, Sydney, NSW, Australia
- NSW Health Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Sydney, NSW, Australia
| | - Roderick Clifton-Bligh
- Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Jenny E. Gunton
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Department of Endocrinology, Westmead Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
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30
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Novel human immunomodulatory T cell receptors and their double-edged potential in autoimmunity, cardiovascular disease and cancer. Cell Mol Immunol 2020; 18:919-935. [PMID: 33235388 DOI: 10.1038/s41423-020-00586-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 10/28/2020] [Indexed: 12/15/2022] Open
Abstract
In the last decade, approaches based on T cells and their immunomodulatory receptors have emerged as a solid improvement in treatments for various types of cancer. However, the roles of these molecules in the therapeutic context of autoimmune and cardiovascular diseases are still relatively unexplored. Here, we review the best known and most commonly used immunomodulatory T cell receptors in clinical practice (PD-1 and CTLA-4), along with the rest of the receptors with known functions in animal models, which have great potential as modulators in human pathologies in the medium term. Among these other receptors is the receptor CD69, which has recently been described to be expressed in mouse and human T cells in autoimmune and cardiovascular diseases and cancer. However, inhibition of these receptors individually or in combination by drugs or monoclonal antibodies generates a loss of immunological tolerance and can trigger multiple autoimmune disorders in different organs and immune-related adverse effects. In the coming decades, knowledge on the functions of different immunomodulatory receptors will be pivotal for the development of new and better therapies with less harmful side effects. In this review, we discuss the roles of these receptors in the control of immunity from a perspective focused on therapeutic potential in not only cancer but also autoimmune diseases, such as systemic lupus erythematosus, autoimmune diabetes and rheumatoid arthritis, and cardiovascular diseases, such as atherosclerosis, acute myocardial infarction, and myocarditis.
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31
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Bagchi S, Yuan R, Engleman EG. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2020; 16:223-249. [PMID: 33197221 DOI: 10.1146/annurev-pathol-042020-042741] [Citation(s) in RCA: 1285] [Impact Index Per Article: 257.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Immune checkpoint inhibitors (ICIs) have made an indelible mark in the field of cancer immunotherapy. Starting with the approval of anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) for advanced-stage melanoma in 2011, ICIs-which now also include antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1)-quickly gained US Food and Drug Administration approval for the treatment of a wide array of cancer types, demonstrating unprecedented extension of patient survival. However, despite the success of ICIs, resistance to these agents restricts the number of patients able to achieve durable responses, and immune-related adverse events complicate treatment. Thus, a better understanding of the requirements for an effective and safe antitumor immune response following ICI therapy is needed. Studies of both tumoral and systemic changes in the immune system following ICI therapy have yielded insight into the basis for both efficacy and resistance. Ultimately, by building on these insights, researchers should be able to combine ICIs with other agents, or design new immunotherapies, to achieve broader and more durable efficacy as well as greater safety. Here, we review the history and clinical utility of ICIs, the mechanisms of resistance to therapy, and local and systemic immune cell changes associated with outcome.
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Affiliation(s)
- Sreya Bagchi
- Department of Pathology, Stanford University School of Medicine, Stanford, California 94304, USA; ,
| | - Robert Yuan
- Department of Pathology, Stanford University School of Medicine, Stanford, California 94304, USA; ,
| | - Edgar G Engleman
- Department of Pathology, Stanford University School of Medicine, Stanford, California 94304, USA; ,
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32
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Nasser NJ, Gorenberg M, Agbarya A. First line Immunotherapy for Non-Small Cell Lung Cancer. Pharmaceuticals (Basel) 2020; 13:ph13110373. [PMID: 33171686 PMCID: PMC7695295 DOI: 10.3390/ph13110373] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 11/04/2020] [Accepted: 11/05/2020] [Indexed: 12/19/2022] Open
Abstract
Immunotherapy for non-small cell lung cancer (NSCLC) is incorporated increasingly in first line treatments protocols. Multiple phase 3 studies have tested different medications targeting programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), with or without chemotherapy. The inclusion criteria differ between the various clinical trials, including the cut-off levels of PD-L1 expression on tumor cells, and the tumor histology (squamous or non-squamous). Patients with tumor expression levels of PD-L1 ≥ 50% are candidates for treatment with single agent Pembrolizumab or Atezolizumab. Patients with PD-L1 < 50% are candidates for immunotherapy with pembrolizumab as a single agent if PL-1 > 1%; immunotherapy doublet, Nivolumab and Ipilimumab, or single agent immunotherapy combined with chemotherapy. Here we review phase 3 clinical trials utilizing immunotherapy in the first line for treatment of NSCLC, including Pembrolizumab in KEYNOTE-024, KEYNOTE-042, KEYNOTE-189 and KEYNOTE-407; Nivolumab and Ipilimumab in CHECKMATE-227 and CHECKMATE 9LA; and Atezolizumab in IMpower110, IMpower130 and IMpower150.
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Affiliation(s)
- Nicola J. Nasser
- Department of Radiation Oncology, University of Maryland School of Medicine, Maryland Proton Treatment Center, Baltimore, MD 21201, USA
- Correspondence: or
| | - Miguel Gorenberg
- Department of Nuclear Medicine, Bnai Zion Medical Center; the Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31048, Israel;
| | - Abed Agbarya
- Institute of Oncology, Bnai Zion Medical Center, Haifa 31048, Israel;
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Stelmachowska-Banaś M, Czajka-Oraniec I. Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review. Endocr Connect 2020; 9:R207-R228. [PMID: 33064663 PMCID: PMC7576644 DOI: 10.1530/ec-20-0342] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 09/16/2020] [Indexed: 12/18/2022]
Abstract
Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.
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Affiliation(s)
- Maria Stelmachowska-Banaś
- Department of Endocrinology, The Centre of Postgraduate Medical Education, Warsaw, Polska, Poland
- Correspondence should be addressed to M Stelmachowska-Banaś:
| | - Izabella Czajka-Oraniec
- Department of Endocrinology, The Centre of Postgraduate Medical Education, Warsaw, Polska, Poland
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34
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Zagouras A, Patil PD, Yogi-Morren D, Pennell NA. Cases from the Immune-Related Adverse Event Tumor Board: Diagnosis and Management of Immune Checkpoint Blockade-Induced Diabetes. Oncologist 2020; 25:921-924. [PMID: 32564463 DOI: 10.1634/theoncologist.2019-0806] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 05/14/2020] [Indexed: 01/15/2023] Open
Abstract
The addition of immune checkpoint inhibitors to the armamentarium of cancer therapies has resulted in unprecedented improvement in clinical outcomes for a vast range of malignancies. Because they interfere with the physiologic function of immune checkpoints, such as programmed cell death protein 1 or cytotoxic T-lymphocyte-associated protein 4, to promote self-tolerance, these agents are associated with a unique spectrum of immune-related adverse events (irAEs). Immune-mediated endocrinopathies are among the most commonly noted irAEs. Immune-mediated diabetes is an uncommon irAE but can be associated with significant morbidity if it is not recognized and treated in a time-sensitive manner. In this manuscript, we present a case based discussion and review of the literature pertaining to immune-mediated diabetes associated with immune checkpoint blockade. KEY POINTS: Immune checkpoint inhibitor associated diabetes mellitus often resembles type 1 diabetes mellitus (DM) in its pathophysiology and clinical manifestations. However, some patients may present with type 2 DM or worsening hyperglycemia in the setting of pre-existent DM. Early recognition and management is key to preventing life-threatening events such as diabetic ketoacidosis. Endocrinology referral and interdisciplinary management should be considered for every patient to optimize glycemic control and to ensure optimal monitoring for long-term microvascular complications.
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Affiliation(s)
- Alexia Zagouras
- Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA
| | - Pradnya D Patil
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland, Ohio, USA
| | - Divya Yogi-Morren
- Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic, Cleveland, Ohio, USA
| | - Nathan A Pennell
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland, Ohio, USA
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Bedrose S, Turin CG, Lavis VR, Kim ST, Thosani SN. A CASE OF ACQUIRED GENERALIZED LIPODYSTROPHY ASSOCIATED WITH PEMBROLIZUMAB IN A PATIENT WITH METASTATIC MALIGNANT MELANOMA. AACE Clin Case Rep 2020; 6:e40-e45. [PMID: 32524008 DOI: 10.4158/accr-2019-0234] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 10/06/2019] [Indexed: 12/17/2022] Open
Abstract
Objective To describe an unusual immune-related adverse event (irAE), acquired generalized lipodystrophy (AGL), from checkpoint inhibitor therapy in a patient treated with pembrolizumab. Methods This is a case report of a 67-year-old male with metastatic melanoma who was treated with pembrolizumab. Prior to pembrolizumab, the patient was treated with another immune-checkpoint inhibitor and developed autoimmune hemolytic anemia. After starting pembrolizumab, he developed a scrotal mass consistent with panniculitis and after several subsequent cycles, he developed AGL. Results Loss of subcutaneous fat, unexplained weight loss in combination with worsening insulin resistance and worsening hypertriglyceridemia after initiation of pembrolizumab were consistent with AGL. Autoimmune disorders and other etiologies were ruled out. Despite this irAE, the patient continued to receive pembrolizumab given stabilization of melanoma with treatment. Conclusion We report the second case of a patient who developed AGL secondary to pembrolizumab, and the fourth case to report such complication secondary to antiprogrammed cell death receptor-1 inhibitors. As use of checkpoint inhibitors becomes more common to treat several types of cancer, it is vital for clinicians to recognize these rare irreversible complications that are not frequently reported in clinical trials.
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Parthymos I, Liamis G, Dounousi E, Pentheroudakis G, Mauri D, Zarkavelis G, Florentin M. Metabolic consequences of immune checkpoint inhibitors: A new challenge in clinical practice. Crit Rev Oncol Hematol 2020; 151:102979. [PMID: 32480349 DOI: 10.1016/j.critrevonc.2020.102979] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 02/29/2020] [Accepted: 05/03/2020] [Indexed: 12/13/2022] Open
Abstract
Treatment of oncologic patients has progressed greatly the last few years with the development of immune checkpoint inhibitors (ICPIs). These drugs are associated with the immune system and, thus, may cause side effects of immune origin, the so called immune related adverse events (irAEs). Immune related AEs may actually affect all organs and systems and frequently resemble clinical entities commonly encountered in clinical practice. As ICPIs have improved both quality of life and life expectancy, clinicians of various specialties may need to deal with irAEs in their everyday practice. Therefore, they should be able to recognize them timely and treat them accordingly. Herein, we review the pathophysiology, clinical manifestations and treatment of irAEs.
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Affiliation(s)
- Ioannis Parthymos
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece
| | - George Liamis
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece
| | - Evangelia Dounousi
- Department of Internal Medicine, Division of Nephrology, School of Medicine, University of Ioannina, Ioannina, Greece
| | - George Pentheroudakis
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece
| | - Davide Mauri
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece
| | - George Zarkavelis
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece
| | - Matilda Florentin
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece.
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Monami M, Naletto L, Nreu B, Dicembrini I, Sesti G, Mannucci E. Immune checkpoints inhibitors and hyperglycemia: A Meta-analysis of randomized controlled trials. Diabetes Res Clin Pract 2020; 162:108115. [PMID: 32179128 DOI: 10.1016/j.diabres.2020.108115] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 01/17/2020] [Accepted: 03/05/2020] [Indexed: 01/27/2023]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICI) exert their therapeutic effect by modulating the immune system and potentiating antitumor immunity. ICI have been associated with several immune-related adverse events, such as diabetes. However, no formal metaanalysis with this respect has been conducted so far. Aim of the present metaanalysis of randomized trials is to assess the effects of ICI on incident diabetes and hyperglycemia. METHODS A MEDLINE, Scopus, ISI-WOS, and Cochrane database search was performed to identify trials, enrolling patients with any form of cancer, up to April 23rd, 2019 in which ICI have been compared either with placebo or active comparators. Data were extracted from published reports or, if not available, from clinicaltrials.gov. The principal endpoints were the incidence of diabetes and cases of hyperglycemia, reported as adverse events. Mantel-Haenszel Odds Ratio with 95% Confidence Interval (MH-OR) was calculated for all outcomes. The study has been registered on PROSPERO website (CDR133927). FINDINGS Out of 42 trials retrieved, 40 reported information on incident diabetes or hyperglycemia. No association of ICI with incident diabetes (MH-OR 1.27 [0.66, 2.43], p = 0.47) was observed; whereas there was a trend toward an increased risk of hyperglycemia (MH-OR 1.45 [0.99, 2.13], p = 0.060), which reached statistical significance in sensitivity analyses and when analyzing separately placebo-controlled trials (MH-OR 1.95 [1.10, 3.49], p = 0.020). I2 statistics did not suggest any relevant heterogeneity for all the principal analyses performed. INTERPRETATION ICI treatment is associated with an increased risk of hyperglycemia, and an increase in the risk of diabetes cannot be excluded.
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Affiliation(s)
- Matteo Monami
- Diabetology, Careggi Hospital and University of Florence, Italy.
| | - Lara Naletto
- Diabetology, Careggi Hospital and University of Florence, Italy
| | - Besmir Nreu
- Diabetology, Careggi Hospital and University of Florence, Italy
| | | | - Giorgio Sesti
- Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy
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Li W, Wang H, Chen B, Zhao S, Zhang X, Jia K, Deng J, He Y, Zhou C. Anti PD-1 monoclonal antibody induced autoimmune diabetes mellitus: a case report and brief review. Transl Lung Cancer Res 2020; 9:379-388. [PMID: 32420079 PMCID: PMC7225154 DOI: 10.21037/tlcr.2020.03.05] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Nowadays, immune checkpoint inhibitor therapy has been used in more and more cancer patients. These agents were associated with immune-related adverse effects, and autoimmune diabetes mellitus is one of them. And it is not common but can be potentially fatal. Anti PD-1 monoclonal antibody is a humanized IgG4 antibody against PD-1, which has been applied in advanced non-small cell lung cancer (NSCLC) treatment. In this paper, we reported the case of autoimmune diabetes mellitus induced by anti PD-1 monoclonal antibody in NSCLC treatment. Here is a 73-year-old male patient with no diabetes history who had anti PD-1 monoclonal antibody 200 mg every 3 weeks for NSCLC treatment. After 10 cycles of the therapy, his blood glucose level elevated and he suffered diabetic ketoacidosis (DKA). And his C-peptide was significantly decreased with negative relative auto-antibodies. Combined with his medical history and the laboratory examination, anti PD-1 monoclonal antibody induced autoimmune diabetes mellitus was diagnosed. After recovering from DKA and controlling his blood glucose, his anti PD-1 therapy was continued and he still got some benefit. This report suggested that glycemic monitoring is imperative during this anti PD-1 monoclonal antibody treatment. Moreover, after controlling the blood glucose level, continuing the immune therapy could still be benefit and safe for the patient.
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Affiliation(s)
- Wei Li
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China
| | - Hao Wang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China.,Tongji University, Shanghai 200433, China
| | - Bin Chen
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China
| | - Sha Zhao
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China.,Tongji University, Shanghai 200433, China
| | - Xiaoshen Zhang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China.,Tongji University, Shanghai 200433, China
| | - Keyi Jia
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China.,Tongji University, Shanghai 200433, China
| | - Juan Deng
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China.,Tongji University, Shanghai 200433, China
| | - Yayi He
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China
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Si X, Song P, Ni J, Di M, He C, Zhang L, Liu X, Li Y, Wang H, Guo X, Zhou J, Duan L, Yang X, Wang M, Zhang L. Management of immune checkpoint inhibitor-related adverse events: A review of case reports. Thorac Cancer 2020; 11:498-504. [PMID: 31970923 PMCID: PMC7049490 DOI: 10.1111/1759-7714.13315] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 12/28/2019] [Accepted: 12/29/2019] [Indexed: 12/20/2022] Open
Abstract
Immune checkpoint inhibitors represent a major breakthrough in cancer therapy. Immune‐related adverse events (irAEs) may occur during treatment due to their unique mechanism of action. Management of irAEs is based on clinical experience because it is not easy to conduct prospective trials to evaluate the best treatment strategy. Using a combination of search terms in the PubMed and Embase databases, we reviewed all cases in the English language citing toxicities associated with either pembrolizumab, nivolumab, ipilimumab, atezolizumab, tremelimumab, durvalumab, avelumab or any combination of these agents published before 20 May 2019. A total of 128 reports with 239 cases were included in the study. Here, we summarize the spectrum of toxicities, safety in special patients, rechallenging after irAEs and agents used for treatment of irAEs in those reports.
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Affiliation(s)
- Xiaoyan Si
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China
| | - Peng Song
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China
| | - Jun Ni
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China
| | - Mingyi Di
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China
| | - Chunxia He
- Department of Dermatology, Peking Union Medical College Hospital, Beijing, China
| | - Li Zhang
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Beijing, China
| | - Xiaowei Liu
- Department of Ophthalmology, Peking Union Medical College Hospital, Beijing, China
| | - Yue Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China
| | - Hanping Wang
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China
| | - Xiaoxiao Guo
- Department of Cardiology, Peking Union Medical College Hospital, Beijing, China
| | - Jiaxin Zhou
- Department of Rheumatology, Peking Union Medical College Hospital, Beijing, China
| | - Lian Duan
- Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China
| | - Xu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Mengzhao Wang
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China
| | - Li Zhang
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China
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40
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Zezza M, Kosinski C, Mekoguem C, Marino L, Chtioui H, Pitteloud N, Lamine F. Combined immune checkpoint inhibitor therapy with nivolumab and ipilimumab causing acute-onset type 1 diabetes mellitus following a single administration: two case reports. BMC Endocr Disord 2019; 19:144. [PMID: 31870373 PMCID: PMC6929418 DOI: 10.1186/s12902-019-0467-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 12/02/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The use of immune checkpoint inhibitor (ICI) therapy is becoming a standard of care for several cancers. Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand (PD-L1) cause a broad spectrum of autoimmune adverse events. ICI-induced type 1 diabetes mellitus (T1DM) is extremely rare (< 1%) but potentially life-threatening. It appears to be more common with PD-1 blockade (or combination immunotherapy) than with anti-CTLA-4 therapy, often during the first three to six months of therapy. CASES PRESENTATION We report an acute onset T1DM with severe inaugural diabetic ketoacidosis (DKA) and remarkably elevated Glutamic Acid Decarboxylase antibody (GADA) titres following a single administration of combined ICI therapy with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in two adult patients with advanced metastatic melanoma. In these cases, the time to diabetes onset was remarkably short (two and five weeks), and one presented with fulminous T1DM in a previous long-standing type 2 diabetes mellitus. CONCLUSIONS Oncological patients treated with combination therapy of anti-PD-1 and anti-CTLA-4 can develop a particular pattern of T1DM, with very rapid onset within a few weeks after starting ICI therapy, even in the presence of an existing type 2 diabetes. ICI-induced T1DM is a medical emergency in presence of severe inaugural DKA and requires a collaboration between specialists and primary care physicians, as well as patient education, for early diagnosis and supportive care.
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Affiliation(s)
- Marco Zezza
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital (CHUV), University of Lausanne, Av. de La Sallaz 8, 1011, Lausanne, Switzerland
| | - Christophe Kosinski
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital (CHUV), University of Lausanne, Av. de La Sallaz 8, 1011, Lausanne, Switzerland
| | - Carine Mekoguem
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital (CHUV), University of Lausanne, Av. de La Sallaz 8, 1011, Lausanne, Switzerland
| | - Laura Marino
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital (CHUV), University of Lausanne, Av. de La Sallaz 8, 1011, Lausanne, Switzerland
| | - Haithem Chtioui
- Service of Clinical Pharmacology, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland
| | - Nelly Pitteloud
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital (CHUV), University of Lausanne, Av. de La Sallaz 8, 1011, Lausanne, Switzerland
| | - Faiza Lamine
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital (CHUV), University of Lausanne, Av. de La Sallaz 8, 1011, Lausanne, Switzerland.
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Marchand L, Disse E, Dalle S, Reffet S, Vouillarmet J, Fabien N, Thivolet C, Cugnet-Anceau C. The multifaceted nature of diabetes mellitus induced by checkpoint inhibitors. Acta Diabetol 2019; 56:1239-1245. [PMID: 31423559 DOI: 10.1007/s00592-019-01402-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Accepted: 08/05/2019] [Indexed: 12/30/2022]
Abstract
Immune checkpoint inhibitors (CPI) are increasingly being used in oncology, and many autoimmune side effects have been described. Diabetes mellitus (DM) has been reported in approximately 1% of subjects treated with programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors, alone or in association with CTLA-4 inhibitors. In the present mini-review, we aimed to describe different clinical pictures and pathophysiology associated with these forms of diabetes. Data on CPI-related DM was gathered from the largest case series in the literature and from our centre dedicated to immunotherapy complications (ImmuCare-Hospices Civils de Lyon). Most cases are acute autoimmune insulin-dependent diabetes which are similar to fulminant diabetes (extremely acute onset with concomitant near-normal HbA1c levels). Other cases, however, have a phenotype close to type 2 diabetes or appear as a decompensation of previously known type 2 diabetes. The occurrence of diabetes can also be a complication of autoimmune pancreatitis induced by CPI use. Finally, two cases of diabetes in a context of autoimmune lipoatrophy have recently been described. Regarding the wide variety of CPI-induced diabetes, the discovery of a glucose disorder under CPI should motivate specialised care for aetiological diagnosis and appropriate treatment.
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MESH Headings
- Autoimmune Diseases/chemically induced
- Autoimmune Diseases/epidemiology
- Autoimmune Diseases/etiology
- B7-H1 Antigen/antagonists & inhibitors
- B7-H1 Antigen/immunology
- CTLA-4 Antigen/antagonists & inhibitors
- CTLA-4 Antigen/immunology
- Cell Cycle Checkpoints/drug effects
- Cell Cycle Checkpoints/immunology
- Diabetes Mellitus, Lipoatrophic/chemically induced
- Diabetes Mellitus, Lipoatrophic/epidemiology
- Diabetes Mellitus, Lipoatrophic/immunology
- Diabetes Mellitus, Type 1/chemically induced
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/diagnosis
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 2/chemically induced
- Diabetes Mellitus, Type 2/diagnosis
- Diabetes Mellitus, Type 2/epidemiology
- Diabetes Mellitus, Type 2/immunology
- Humans
- Immunotherapy/adverse effects
- Protein Kinase Inhibitors/adverse effects
- Protein Kinase Inhibitors/therapeutic use
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Affiliation(s)
- Lucien Marchand
- Department of Endocrinology and Diabetes, St. Joseph - St. Luc Hospital, Quai Claude Bernard, 69007, Lyon, France.
| | - Emmanuel Disse
- Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre-Bénite, France
- CarMeN Laboratory (INSERM U1060, INRA U1235, Université Claude Bernard Lyon1, INSA-Lyon), Lyon 1 University, Oullins, France
| | - Stéphane Dalle
- Department of Dermatology, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre-Bénite, France
- ImmuCare (Immunology Cancer Research), Hospices Civils de Lyon, Lyon, France
| | - Sophie Reffet
- Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre-Bénite, France
| | - Julien Vouillarmet
- Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre-Bénite, France
| | - Nicole Fabien
- Department of Immunology, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre-Bénite, France
| | - Charles Thivolet
- Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre-Bénite, France
- CarMeN Laboratory (INSERM U1060, INRA U1235, Université Claude Bernard Lyon1, INSA-Lyon), Lyon 1 University, Oullins, France
| | - Christine Cugnet-Anceau
- Department of Endocrinology and Diabetes, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre-Bénite, France
- ImmuCare (Immunology Cancer Research), Hospices Civils de Lyon, Lyon, France
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Immune Checkpoint Inhibitor Induced Diabetes Mellitus Treated with Insulin and Metformin: Evolution of Diabetes Management in the Era of Immunotherapy. Case Rep Oncol Med 2019; 2019:8781347. [PMID: 31781446 PMCID: PMC6875347 DOI: 10.1155/2019/8781347] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 10/26/2019] [Indexed: 11/18/2022] Open
Abstract
Immune checkpoint inhibitors (ICPIs) are a breakthrough therapy in oncology and have been approved by the Food and Drug Administration for the treatment of several malignancies. ICPIs have been reported to cause immune-mediated damage of islet cells leading to ICPI-induced type 1 diabetes mellitus (T1DM). These reports described patients presenting with severe diabetic ketoacidosis (DKA). We present a case of a 69-year-old Caucasian male with type 2 diabetes suffering from non-small cell lung cancer and undergoing treatment with pembrolizumab, an anti-programmed cell death protein-1 antibody, who presented to our emergency department with complaints of nausea, vomiting, polyuria, and polydipsia. He was found to have high anion gap metabolic acidosis with ketosis and elevated blood glucose levels consistent with DKA. Lab workup was consistent with T1DM. Despite being on a tailored insulin regimen, his blood glucose remained elevated, necessitating the addition of metformin to his regimen which effectively controlled his blood glucose.
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Simeone E, Grimaldi AM, Festino L, Trojaniello C, Vitale MG, Vanella V, Palla M, Ascierto PA. Immunotherapy in metastatic melanoma: a novel scenario of new toxicities and their management. Melanoma Manag 2019; 6:MMT30. [PMID: 31871619 PMCID: PMC6920742 DOI: 10.2217/mmt-2019-0005] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 07/18/2019] [Indexed: 12/13/2022] Open
Abstract
Checkpoint inhibitors can cause an imbalance in immune tolerance that may clinically manifest as immune-related adverse events (irAEs). These events may involve many organs and tissues, including the skin, gastrointestinal (GI) tract, liver, endocrine system, kidneys, central nervous system (CNS), eyes and lungs. The incidence of irAEs appears to be lower with anti-programmed death antigen-1/programmed death antigen-ligand-1 agents than with the anti-cytotoxic T-lymphocyte-associated protein-4 antibody ipilimumab. Combined immunotherapy does not appear to be associated with novel safety signals compared with monotherapy, but more organs may be involved. Increased experience and the use of algorithms for the most common irAEs have resulted in severe toxicity and related deaths being reduced. However, continuous vigilance, especially regarding less common events, is needed to better characterize the wide spectrum of clinical manifestations.
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Affiliation(s)
- Ester Simeone
- Unit of Melanoma, Cancer Immunotherapy & Innovative Therapies Unit – Istituto Nazionale Tumori Fondazione ‘G. Pascale,’ IRCCS, 80131, Napoli, Italy
| | - Antonio M Grimaldi
- Unit of Melanoma, Cancer Immunotherapy & Innovative Therapies Unit – Istituto Nazionale Tumori Fondazione ‘G. Pascale,’ IRCCS, 80131, Napoli, Italy
| | - Lucia Festino
- Unit of Melanoma, Cancer Immunotherapy & Innovative Therapies Unit – Istituto Nazionale Tumori Fondazione ‘G. Pascale,’ IRCCS, 80131, Napoli, Italy
| | - Claudia Trojaniello
- Unit of Melanoma, Cancer Immunotherapy & Innovative Therapies Unit – Istituto Nazionale Tumori Fondazione ‘G. Pascale,’ IRCCS, 80131, Napoli, Italy
| | - Maria G Vitale
- Unit of Melanoma, Cancer Immunotherapy & Innovative Therapies Unit – Istituto Nazionale Tumori Fondazione ‘G. Pascale,’ IRCCS, 80131, Napoli, Italy
| | - Vito Vanella
- Unit of Melanoma, Cancer Immunotherapy & Innovative Therapies Unit – Istituto Nazionale Tumori Fondazione ‘G. Pascale,’ IRCCS, 80131, Napoli, Italy
| | - Marco Palla
- Unit of Melanoma, Cancer Immunotherapy & Innovative Therapies Unit – Istituto Nazionale Tumori Fondazione ‘G. Pascale,’ IRCCS, 80131, Napoli, Italy
| | - Paolo A Ascierto
- Unit of Melanoma, Cancer Immunotherapy & Innovative Therapies Unit – Istituto Nazionale Tumori Fondazione ‘G. Pascale,’ IRCCS, 80131, Napoli, Italy
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Lu JG, Ji P, French SW. The Major Histocompatibility Complex Class II-CD4 Immunologic Synapse in Alcoholic Hepatitis and Autoimmune Liver Pathology: The Role of Aberrant Major Histocompatibility Complex Class II in Hepatocytes. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 190:25-32. [PMID: 31669415 DOI: 10.1016/j.ajpath.2019.09.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 08/27/2019] [Accepted: 09/24/2019] [Indexed: 12/12/2022]
Abstract
The major histocompatibility complex class II (MHC II)-CD4 immunologic synapse is classically described between the T-cell receptor of CD4-positive lymphocytes and MHC II on antigen-presenting cells. This interaction and others between surrounding costimulatory and checkpoint molecules promote differentiation of naïve CD4 T lymphocytes into helper T cells subtypes, including types 1, 2, and 17 helper T cells, that have more tailored immunologic responses. Although MHC II is mainly produced by professional antigen-presenting cells, it can be aberrantly produced by other cell types, including hepatocytes in various liver pathologies, such as autoimmune hepatitis and alcoholic hepatitis. This can lead to direct targeting of hepatocytes by CD4-positive lymphocytes, which form an immunologic synapse with the hepatocyte. The lymphocytes internalize the MHC II-CD4 complexes in a phagocytosis-like mechanism and in the process eat the hepatocyte piece by piece. We review the evidence for this mechanism and the role of these autoimmune responses in various liver diseases, including alcoholic hepatitis, autoimmune hepatitis, and primary biliary cirrhosis. The role of aberrant MHC II in malignancy, including hepatocellular carcinoma, is also reviewed. Further understanding of this mechanism can lead to better understanding of the immune mechanisms involved in these liver pathologies, with potential diagnostic and therapeutic applications.
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Affiliation(s)
- Jiajie G Lu
- Department of Pathology, Harbor-UCLA Medical Center, Torrance, California.
| | - Ping Ji
- Department of Pathology, Harbor-UCLA Medical Center, Torrance, California
| | - Samuel W French
- Department of Pathology, Harbor-UCLA Medical Center, Torrance, California
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Yamamoto N, Tsurutani Y, Katsuragawa S, Kubo H, Sunouchi T, Hirose R, Hoshino Y, Ichikawa M, Takiguchi T, Yukawa H, Arioka H, Saitou J, Nishikawa T. A Patient with Nivolumab-related Fulminant Type 1 Diabetes Mellitus whose Serum C-peptide Level Was Preserved at the Initial Detection of Hyperglycemia. Intern Med 2019; 58:2825-2830. [PMID: 31243198 PMCID: PMC6815891 DOI: 10.2169/internalmedicine.2780-19] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
A 77-year-old-man with renal cell carcinoma who was undergoing nivolumab treatment visited our department due to hyperglycemia; his plasma glucose level was 379 mg/dL. Although his serum C-peptide immunoreactivity (CPR) level was preserved (5.92 ng/mL), we suspected an onset of fulminant type 1 diabetes mellitus (FT1DM) and immediately started insulin therapy. His CPR levels gradually decreased and were depleted within 1 week. We later discovered that the patient's casual CPR level had been abnormally high (11.78 ng/mL) 2 weeks before his admission. Hence, the possibility of FT1DM in hyperglycemic patients undergoing nivolumab treatment should not be excluded, even with a preserved CPR level.
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Affiliation(s)
- Naoko Yamamoto
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Japan
| | - Yuya Tsurutani
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Japan
| | - Sho Katsuragawa
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Japan
| | - Haremaru Kubo
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Japan
| | - Takashi Sunouchi
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Japan
| | - Rei Hirose
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Japan
| | | | | | - Tomoko Takiguchi
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Japan
| | - Hiroko Yukawa
- Department of Medical Oncology, Yokohama Rosai Hospital, Japan
| | - Hitoshi Arioka
- Department of Medical Oncology, Yokohama Rosai Hospital, Japan
| | - Jun Saitou
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Japan
| | - Tetsuo Nishikawa
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Japan
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Abstract
Acute type 1 diabetes (AD1) is a rare but definitive immune-related adverse event associated with anti-PD1. Most of the reported cases are close to what has been described as "fulminant type 1 diabetes." We sought to determine whether anti-PD1 could impair glycoregulation and whether occurrence of AD1 could be anticipated by prior glycemic changes. Fasting glycemia collected before, under, and after treatment in melanoma patients treated with anti-PD1 over a period of 36 months were retrospectively analyzed. Glycemic trend analyses were performed using linear regression analysis. In total, 1470 glucose values were monitored in 163 patients treated for a mean duration of 5.96 months. Three patients developed an AD1 (1, 84%). Two other cases were observed in the same period in a still-blinded trial of anti-PD1 versus ipilimumab. All cases of AD1 occurred in patients with a normal pretreatment glycemia, and there was no detectable drift of glycemia before ketoacidosis onset. In 4 of 5 cases of AD1, the HLA subgroups were DRB01* 03 or 04, known to increase type 1 diabetes risk in the general population. In the 28 patients with preexisting type 2 diabetes, there was a slight trend for glycemia increase with anti-PD1 infusions (0.05 mmol/L/infusion P=0.004). In the 132 patients with normal pretreatment glycemia, there was a slight trend for a decrease of glycemia with anti-PD1 infusions (-0.012/mmol/L/infusion P=0.026). These data suggest that the monitoring of glycemia under anti-PD1 cannot help to anticipate AD1, and there is no general tendency to glycemic disorder. HLA genotyping before treatment may help to focus surveillance in patients with the HLA DRB1*03/04 group.
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de Filette JMK, Pen JJ, Decoster L, Vissers T, Bravenboer B, Van der Auwera BJ, Gorus FK, Roep BO, Aspeslagh S, Neyns B, Velkeniers B, Kharagjitsingh AV. Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review. Eur J Endocrinol 2019; 181:363-374. [PMID: 31330498 PMCID: PMC6709545 DOI: 10.1530/eje-19-0291] [Citation(s) in RCA: 172] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 07/19/2019] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs). DESIGN AND METHODS We report the case of a lung cancer patient with diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy. RESULTS Our literature search identified 90 patient cases (our case excluded). Most patients were treated with anti-PD-1 or anti-PD-L1 as monotherapy (79%) or in combination with CTLA-4 blockade (15%). On average, diabetes mellitus was diagnosed after 4.5 cycles; earlier for combination ICI at 2.7 cycles. Early-onset diabetes mellitus (after one or two cycles) was observed during all treatment regimens. Diabetic ketoacidosis was present in 71%, while elevated lipase levels were detected in 52% (13/25). Islet autoantibodies were positive in 53% of patients with a predominance of glutamic acid decarboxylase antibodies. Susceptible HLA genotypes were present in 65% (mostly DR4). Thyroid dysfunction was the most frequent other endocrine AE at 24% incidence in this patient population. CONCLUSION ICI-related diabetes mellitus is a rare but often life-threatening metabolic urgency of which health-care professionals and patients should be aware. Close monitoring of blood glucose and prompt endocrine investigation in case of hyperglycemia is advisable. Predisposing factors such as HLA genotype might explain why some individuals are at risk.
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Affiliation(s)
| | - Joeri J Pen
- Diabetes Clinic, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Lore Decoster
- Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Thomas Vissers
- Medical Library, Haaglanden Medical Center, Hague, The Netherlands
| | - Bert Bravenboer
- Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | | | - Frans K Gorus
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Bart O Roep
- Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
- Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, City of Hope, Duarte, California, USA
| | - Sandrine Aspeslagh
- Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Bart Neyns
- Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Brigitte Velkeniers
- Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Aan V Kharagjitsingh
- Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels, Belgium
- Diabetes Clinic, Universitair Ziekenhuis Brussel, Brussels, Belgium
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
- Section Endocrinology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Abstract
OBJECTIVES To discuss future direction and present an overview of the evolution of immunotherapy long-term toxicity issues, financial toxicity, and new emerging survivorship considerations. DATA SOURCES Peer-reviewed manuscripts, Web sites. CONCLUSION Cancer treatments involving immunotherapy have had a major impact on long-term survival, toxicity, and survivorship issues. IMPLICATIONS FOR NURSING PRACTICE Nurses play a pivotal role in the care of the cancer patient across the continuum. With the unique toxicities associated with immunotherapy, it is essential that nurses be keenly aware of all aspects of management, from physical to financial care.
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49
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Hoefsmit EP, Rozeman EA, Haanen JBAG, Blank CU. Susceptible loci associated with autoimmune disease as potential biomarkers for checkpoint inhibitor-induced immune-related adverse events. ESMO Open 2019; 4:e000472. [PMID: 31423333 PMCID: PMC6677983 DOI: 10.1136/esmoopen-2018-000472] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 03/01/2019] [Accepted: 03/19/2019] [Indexed: 12/13/2022] Open
Abstract
Unprecedented successes regarding cancer immunotherapy have been achieved, in which therapeutic agents are used to target immune cells rather than cancer cells. The most effective immunotherapy to date is the group of immune checkpoint inhibitors (CPI), targeting, for example, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death protein (PD-1). TThe combination of these therapies (anti-PD-1 with anti-CTLA-4) induces high response rates, and seem to be increased further when applied in early-stage disease. However, combined CTLA-4 plus PD-1 blockade causes frequent high-grade immune-related adverse events (irAE). To date, research on biological mechanism of irAEs is scarce and no widely accepted biomarkers predicting onset of severe irAEs have been identified. The similarity of irAEs to autoimmune disorders fuels the hypothesis that irAEs may be linked to susceptible genetic loci related to various autoimmune diseases. In this review, we extensively searched for susceptible loci associated with various autoimmune diseases, and pooled them in groups most likely to be associated with CPI-induced irAEs. These sets could be used in future research on predicting irAEs and guide physicians in a more refined and personal manner.
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Affiliation(s)
- Esmée P Hoefsmit
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Elisa A Rozeman
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Medical Oncology Department, Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands
| | - John B A G Haanen
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Medical Oncology Department, Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands
| | - Christian U Blank
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.,Medical Oncology Department, Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands
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50
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Boyle V, Cundy T, Cutfield R. Rapid onset type 1 diabetes associated with the programmed cell death-1 inhibitor pembrolizumab. Intern Med J 2019; 49:930-931. [PMID: 31295781 DOI: 10.1111/imj.14340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/08/2018] [Accepted: 11/10/2018] [Indexed: 11/28/2022]
Affiliation(s)
- Veronica Boyle
- Diabetes Centre, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand
| | - Tim Cundy
- Diabetes Centre, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand
| | - Richard Cutfield
- Diabetes Centre, Waitakere and North Shore Hospital Diabetes Centre, Waitemata District Health Board, Auckland, New Zealand
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